Methods for Non-Invasive Assessment of Genomic Instability

Patent metadata

Field	Value
Publication number	US-2023187021-A1
Application number	US-202218045279-A
Country	US
Kind code	A1
Filing date	Oct 10, 2022
Priority date	Jul 27, 2016
Publication date	Jun 15, 2023
Grant date	—

Abstract

Technology provided herein relates in part to methods, processes, machines and apparatuses for non-invasive assessment of genomic nucleic acid instability and genomic nucleic acid stability.

First claim

1 - 42 . (canceled)

43 . A method of determining presence or absence of genomic instability for a test subject, comprising:
(a) mapping thousands to millions of sequence reads obtained from a nucleic acid sample obtained from the subject to a plurality of genomic portions of a reference genome to generate sequence read quantifications, (b) adjusting the sequence read quantification to reduce experimental bias, thereby generating adjusted sequence read quantifications, (c) generating a genome profile plot of the nucleic acid sample with chromosome-specific shading. representing the adjusted sequence read quantifications in one or more autosomes, (d) determining the absolute deviation from expectation for genomic portions in each of the one or more autosomes, (e) determining an area representing the absolute deviation from expectation for genomic portions in each of the one or more autosomes, and (f) summing the areas representing the absolute deviation from expectation for genomic portions in one or more autosomes, thereby determining a genomic instability number (GIN) for the test sample.

44 . The method of claim 43 , wherein the sample nucleic acid from the subject is circulating cell free nucleic acid.

45 . The method of claim 43 , wherein the sample nucleic acid from the subject is a liquid biopsy sample.

46 . The method of claim 43 , wherein adjusting the sequence read quantification is performed by one or more of SPCA, a GC normalization process, and a smoothing process.

47 . The method of claim 43 , wherein adjusting the sequence read quantifications are performed by SPCA.

48 . A method of determining presence or absence of genomic instability for a test subject, comprising:
(a) mapping thousands to millions of sequence reads obtained from a nucleic acid sample obtained from the subject to a plurality of genomic portions of a reference genome to generate sequence reads quantification (b) adjusting the sequence reads quantification to reduce experimental bias, thereby generating adjusted sequence read quantification, (c) modifying the adjusted sequence read quantifications according to a baseline adjusted sequence read quantification for each of the genomic portions, thereby providing a modified product for each of the genomic portions.

49 . The method of claim 48 , wherein the generating a genomic instability number comprises subtracting a baseline adjusted sequence read quantifications from the adjusted sequence read quantifications for each of the genomic portions, thereby providing a subtraction product for each of the genomic portions.

50 . The method of claim 49 , further comprising determining the absolute value of the modified product or the subtraction product for each of the genomic portions.

51 . The method of claim 49 , wherein the baseline is (i) an average sequence read quantifications for the genomic portions, (ii) a centered value of the sequence read quantifications for the genomic portions, or (iii) a representative value of the sequence read quantifications for the genomic portions.

52 . The method of claim 48 , further comprising scaling the sequence read quantifications for the genomic portions to the average, centered value or representative value of the sequence read quantifications.

53 . The method of claim 48 , wherein the generating a genomic instability classification comprises summing the modified products, absolute values of the modified products, subtraction products or absolute values of the subtraction products for the genomic portions, thereby providing a genomic instability number.

54 . The method of claim 48 , wherein the adjusting comprises normalizing the quantification of sequence reads by a guanine-cytosine (GC) normalizing process that generates a GC normalized quantification of sequence reads for each of the genomic portions, whereby the sequence read quantifications in (b) is the GC normalized quantification of sequence reads.

55 . The method of claim 48 , wherein the adjusting the sequence read quantification is performed by one or more of SPCA, a GC normalization process, and a smoothing process.

56 . The method of claim 48 , wherein the adjusting the sequence read quantification is performed SPCA.

57 . The method of claim 43 , wherein the subject is diagnosed with a cell proliferative condition according to the genomic instability number, and the subject is selected for a treatment of the cell proliferative condition according to the genomic instability number.

58 . The method of claim 57 , wherein the genomic instability number is generated for the subject at two or more time points during the treatment, and (i) the subject is identified as a responder to the treatment if after a time point of about 6 weeks to about 8 weeks of treatment the genomic instability number is less than a threshold value, or (ii) the subject is identified as a non-responder to the treatment if after the time point of treatment the genomic instability number is greater than the threshold value.

59 . The method of claim 57 , wherein the cell proliferative disorder is a cancer.

60 . The method of claim 57 , wherein the treatment comprises administering at least one of an immunotherapeutic.

61 . A method of evaluating the clinical effectiveness of a cancer therapy treatment comprising
a) obtaining two or more nucleic acid samples from two or more time points during the treatment, b) determining a GIN for each of the two or more nucleic acid samples using the method of claim 43 , thereby generating GINs corresponding to samples from two or more time points during the treatment, wherein a decrease in GIN during the treatment indicates that the treatment is effective.

Assignees

• Sequenom Inc

Inventors

• Sun Youting
• Kim Sung Kyun
• Ehrich Mathias
• Ellison Christopher
• Jensen Taylor
• Mazloom Amin

Classifications

• G16B20/00 Primary

  ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations · CPC title

• G16B10/00

  ICT specially adapted for evolutionary bioinformatics, e.g. phylogenetic tree construction or analysis · CPC title

• G16B20/20

  Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection · CPC title

• G16B20/10 Primary

  Ploidy or copy number detection · CPC title